Objectives

Background

Bronchopulmonary dysplasia (BPD) is the most common form of chronic lung disease in children with an estimated 15,000 new cases annually in the United States. BPD affects infants born prematurely, is a major contributor to the cost of prematurity each year, and is associated with long-term pulmonary disability, neurodevelopmental abnormalities and death.

Increases in the survival of extremely low gestational age infants (ELGANs, ≤28 week gestation) have resulted in another form of BPD, which is characterized by impaired alveolar and microvascular development with excess tone and reactivity of airway smooth muscle.

Despite treatments to enhance lung maturation, premature infants often need prolonged intubation and mechanical ventilation and/or oxygen support. When mechanical ventilation is required longer than 7 days, BPD results in 70% of surviving ELGANs. Most of these infants experience clinical episodes of increased requirement for ventilatory support that are associated with dysfunctional surfactant, which is primarily due to low surfactant protein B (SP-B). In pilot studies of late surfactant treatment in premature infants there was short-term improvement in SP-B content. These prior studies provided the rationale for a larger clinical trial for later doses of surfactant treatment to prevent episodes of respiratory decompensation and BPD.

Subjects

Infants that were born at ≤ 28 0/7 weeks were screened at 25 US centers for the TOLSURF trial. Eligibility was defined as ELGAN infants who required mechanical ventilation at 7-14 days. Of the 2693 infants screened, 511 were eligible for randomization. Of the 511 infants eligible for randomization, there were 252 infants allocated to the treatment arm and 259 infants allocated to the placebo arm.

Infants were excluded from TOLSURF if they had life threatening congenital abnormalities, were clinically unstable, had bilateral grade 4 Intraventricular hemorrhage (IVH) or were unlikely to be available for long-term pulmonary and neurodevelopmental follow-up.

Design

The study was designed to assess the effect of late doses of surfactant on survival without BPD at 36 weeks post menstrual age (PMA) in ELGANs who required intubation and mechanical ventilation between 7 and 14 days of age and were receiving Inhaled nitric oxide (iNO). Infants were stratified within clinical centers and gestational age groups and randomized to treatment with calfactant, a natural surfactant extracted from bovine lung lavage fluid, or a sham procedure.

All infants received iNO according to the protocol used in the NOCLD trial. A masked syringe containing either a standard dose of calfactant for the treatment group, or air for the placebo group, was administered to the infant behind a screen by staff not involved in providing the infant’s clinical care. Monitor and ventilator alarms were turned off during dosing to avoid unblinding of clinical staff. To accommodate research staff availability and infant instability, the dosing interval was not strictly set but could be repeated every 24 – 72 hours up to 5 doses if the infant still required intubation. Dosing could be discontinued by physician request or parental withdrawal from the study. Due to parental preference, the first infant in a multiple birth was randomized according to the randomization schedule and subsequent infants were assigned to the same treatment group. Follow-up to assess pulmonary and neurologic development continued until 2 years of age, with treatment group blinding maintained.

The primary outcome was survival without BPD at 36 weeks PMA. Secondary outcomes included BPD at 40 weeks PMA, pulmonary outcome at 12–24 months of age, and neurodevelopmental outcome at 2 years of age.

Conclusions

There were no significant differences observed between the treatment group and the control group for survival without BPD at 36 weeks or 40 weeks.

Study Documents

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